Tuberculosis is one of major infectious diseases seriously harming human life and health, and also becomes the number-one killer in infectious diseases and the leading cause of death for adults. In the late 1990s, due to drug-resistant bacteria and other issues, the tuberculosis which had disappeared made a comeback throughout the world, which increased difficulties in controlling the tuberculosis. The World Health Organization has made preliminary statistics showing that 1.9 billion people around the world are infected by tuberculosis bacilli, the number of patients with tuberculosis has been up to about 20 million, the number of new cases is up to 8 million each year, and 3 million people on average die from tuberculosis each year. In China, the number of patients infected by tuberculosis bacilli are also rising, and tuberculosis presents an upward trend, the number of patients with tuberculosis ranks the second in the world, and the number of deaths due to tuberculosis each year is about 150,000; prevention and treatment of tuberculosis is a major issue that needs to be resolved urgently, and therefore research and development of new anti-tuberculosis drugs and new dosage forms is imminent.
Mycobacterium tuberculosis mainly parasitizes in normal cells and has some resistance to drugs, and Mycobacterium tuberculosis can be killed only when concentration of an anti-tuberculosis drug in the cell reaches a certain level. Oral formulations of anti-tuberculosis drugs are often influenced by the first-pass effect firstly, and subjected to protein binding, metabolism, excretion, decomposition and other processes during circulating around the body, but only a small amount of drug can reach the target tissue, target organ and target cell, therefore, in order to improve concentration of the drug in the target area, dose of the drug must be increased, which enhances systemic toxic and side effects of the drug. Targeted formulations have characteristics such as directionally releasing drugs, increasing concentration of drugs in lesion sites and cells, improving efficacy, reducing toxic and side effects, therefore it is considered that the anti-tuberculosis drug targeted formulations have clinical application value and development prospects.
Moxifloxacin, which belongs to the fourth-generation chemically synthesized antibiotic drugs of fluoroquinolones, is a product launched by Bayer (Germany) in 1999. Moxifloxacin blocks replication of DNA by inhibiting activities of bacterial DNA gyrase A subunit and topoisomerase IV to play roles in killing bacteria. For gram-negative bacteria, moxifloxacin mainly inhibits the DNA gyrase, and for gram-positive bacteria, the primary action target is the topoisomerase IV. Chemical structure of moxifloxacin is characterized in that the methoxyl is introduced to the 8th carbon atom, which increases the drug's capability of binding to the bacteria and capability of penetrating and destroying the cell membrane, and its post-antibiotic effect (PAE) is strong and lasting.
Moxifloxacin retains antibacterial activity and antibacterial spectrum of quinolone drugs on gram-negative bacteria, and the methoxyl at the 8th carbon atom increases antibacterial activity and broadens antibacterial spectrum of moxifloxacin on gram-positive bacteria. Moxifloxacin is extremely effective to atypical pathogens such as mycoplasma pneumoniae, chlamydia, and legionella, and has strong activity on anaerobic bacteria, for example, it has significant antibacterial activity on anaerobic bacteria with or without spores. Moxifloxacin is also effective to bacteria which are resistant to antibiotics of β-lactams, macrolides, amino glycopeptides and tetracyclines. Moxifloxacin, different from the hepatic cytochrome P-450 isozyme inhibitor, has no drug cross-resistance with these antibiotic drugs, thus avoiding many potential interactions between drugs. Moxifloxacin has similar early bactericidal activity to isoniazid (INH) or rifampin, and has bactericidal activity for early and extended early stage of patients with pulmonary tuberculosis, which shows that moxifloxacin can well penetrate into the tuberculosis lesion sites and quickly kill the fast growing flora in the sputum of patients with severe cavitary pulmonary tuberculosis.
Since it is on the market, moxifloxacin has been widely applied clinically due to its advantages such as broad antibacterial spectrum, strong antibacterial power, wide distribution in the body, high drug concentration in the body, long half-life, good efficacy, little side effects, no drug cross-resistance with other antibacterial drugs, almost no photosensitive reactions and the like. With wide application of anti-tuberculosis drugs clinically, drug resistance of Mycobacterium tuberculosis gets higher and higher, especially the problem of multi-drug resistance, which has become a subject of concern for the anti-tuberculosis field, and is also a main factor impacting chemotherapy effect on tuberculosis. Therefore, selecting an appropriate dosage form of an anti-tuberculosis drug is important for the current treatment and control of tuberculosis.
Phenomenon of recurrence of tuberculosis and drug resistance of tuberculosis bacilli is becoming more and more serious, despite that there are complex causes for the occurrence of the phenomenon, a very important factor is long treatment course, making patients be unable to take medicine with full amount regularly till the end of treatment, which is a common problem faced in the treatment of tuberculosis in countries of the world. On the premise of ensuing therapeutic effect, the problem of drug compliance can be effectively resolved by reducing dose of a drug and prolonging intervals of administration. In order to obtain an anti-tuberculosis drug formulation which can play a long-lasting effect in human body, we have selected a natural polymer, sodium alginate, with good biocompatibility as a carrier and moxifloxacin as a model drug, to crosslink with an adsorbent, so as to obtain a vascular embolic agent containing sustained-release biodegradable microspheres by prescription selection, release experiments in vitro and studies in vivo.
There are only sporadic reports about study on microspheres carrying an anti-tuberculosis drug at home, most of drugs reported are drugs to be administered orally or by injection. At abroad, systematic study reports about microspheres carrying an anti-tuberculosis drug are mainly concentrated in study groups of America, Japan and India, involving different carriers, different drugs, different microsphere size and different routes of administration. Some scholars were dedicated to study on the anti-tuberculosis sustained-release system before, mainly involving oral agents, inhalants, injections, and subdermal implants.
Currently, clinical anti-tuberculosis drugs are mainly oral and injectable formulations, and the efficacy of the injectable formulation is not ideal. Application of anti-tuberculosis drugs is greatly limited since effective drug concentration cannot be obtained at the lesion site and significant systemic toxicity and drug resistance occur in the application process. A few therapies of embolism plus drug infusion have the following defects: the drug cannot be sustainedly released in a relatively uniform form, and the “shock wave” efficacy of the drug may cause necrosis or damage to local tissues when local drug infusion concentration is too high.
Anti-tuberculosis drug microsphere vascular embolic agent is a new dosage form, wherein microspheres deposit in the lung, which can delay release of the drug, protect the drug from being destroyed by enzyme hydrolysis, and prolong retention time of the drug in the lung, and also has advantages in low incidence rate of side effects, good toleration and safety. At present, there has been no reports at home and abroad about an anti-tuberculosis vascular embolic agent prepared by crosslinking moxifloxacin with sodium alginate and an adsorbent, and about application of the anti-tuberculosis vascular embolic agent in treating patients with pulmonary tuberculosis, mass hemoptysis of pulmonary tuberculosis, pulmonary tuberculosis cavity, bronchial stenosis of pulmonary tuberculosis, multi-drug resistant cavitary pulmonary tuberculosis, renal tuberculosis, thyroid tuberculosis, genital tuberculosis (fallopian tube tuberculosis, endometrium tuberculosis, testis tuberculosis, epididymis tuberculosis), cervical lymph node tuberculosis, pericardial tuberculosis, chest wall tuberculosis, and other tuberculosises of other parts in the whole body through interventional embolization.
Moxifloxacin belongs to the fourth-generation chemical antibiotic drugs of fluoroquinolones, with poor solubility in water and organic solvents. Oral and injectable formulations of moxifloxacin are usually applied clinically and have defects as follows: amount of oral absorption is small, dose of injection is low, an effective drug concentration cannot be obtained at the lesion site, releasing cannot be performed in a relatively uniform and sustained form, and adverse reactions are easily caused.